This invention relates to herbal compositions. More particularly, this invention relates to an herbal composition capable of reducing inflammation in bones and joints. The present invention further relates to methods of using such herbal composition to reduce inflammation.
Arthritic disorders, including rheumatism, osteoarthritis, dysplasia, lupus, bursitis, and gout, are all characterized by inflammation and pain in bones, joints, muscles, and related connective tissues. Most of the forms are progressive. Bone and joint inflammation is a scourge of both animals and humans. Those who suffer from inflammation experience pain and discomfort and may, in advanced cases, lose the effective use of inflamed joints. Thus, the goal of therapeutic methods for treating bone or joint inflammation is the relief of pain and discomfort and the restoration of use of inflamed joints.
Certain enzymes appear to play a role in causing inflammation. One of the features of inflammation is increased oxygenation of arachidonic acid which is metabolized by two enzymic pathways--the cyclooxygenase (CO) and the 5-lipoxygenase (5-LO) pathways--leading to the production of prostaglandins and leukotrienes, respectively. Prostaglandins and leukotrienes are mediators of inflammation. Therapies designed to inhibit cydooxygenase and/or lipoxygenase activity are therefore of great interest.
There are two forms of the cyclooxygenase enzyme: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The latter form, i.e., COX-2, appears to play a key role in inflammatory processes. Recent scientific studies suggest that inhibiting the COX-2 enzyme may be an effective wayto reduce inflammation without the side effects associated with irreversible COX-1 inhibition. In addition, recent scientific studies also suggest that COX-2 inhibition may serve an important function in promoting normal cell growth in the colon, pancreas, breast tissue and other organ systems.
Drugs are being developed which are intended to selectively inhibit COX-2 with minimal effect on COX-1. However, despite the emphasis on COX-2 inhibition, these drugs appear to have serious side effects, e.g., a breakdown in digestive protective mucus and prevention of normal healing processes. For example, non-steroidal anti-inflammatory drugs (NSAIDS) can have a variety of toxic side effects such as, e.g., gastric erosion and adverse effects on kidneys and liver, and may inadequately regulate the cellular immune functions and secretions of various cytokines.
Natural ingredients, e.g., herbs, have also been used to treat bone and joint inflammation, especially in eastern countries, and, increasingly, in western countries. Compositions composed of natural ingredients and said to be useful in reducing inflammation are disclosed, e.g., in U.S. Pat. Nos. 5,494,668, 5,683,698, 5,916,565, 5,888,514, 5,908,628; 5,788,971; 5,854,291; and 5,910,307.
U.S. Pat. No. 5,494,668 (Patwardhan) discloses a method of treating degenerative musculoskeletal diseases such as rheumatoid arthritis and osteoarthritis in an animal, typically a human, involving administering to the animal, typically enterally, in a convenient dosage form, a therapeutically effective amount of the beneficiated extracts of the plants Ashwagandha, Sallai Guggul, Turmeric, and Ginger, in a predetermined proportion relative to each other with or without other biologically active inorganic ingredients.
U.S. Pat. No. 5,683,698 (Chavali et al.) discloses an herbal formulation and its use for reducing/alleviating symptoms associated with rheumatoid arthritis, osteoarthritis, and reactive arthritis and for reducing the production of pro-inflammatory cytokines. The formulation contains an herbal extract from the roots, rhizomes and/or vegetation of six herbal plant varieties, specifically, the species of Alpinia, Smilax, Tinospora, Tribulus, Withania, and Zingiber. The patent further discloses foods, beverages and medicaments in the form of capsules, tablets, liquids, and the like, containing the herbal formulation.
U.S. Pat. No. 5,916,565 (Rose et al.) discloses an orally administered composition for prophylaxis and therapy of joint and connective tissue disorders in vertebrates, wherein the composition contains metabolic precursors, herbal phytochemicals, and palatability agents. Suitable herbal phytochemicals are said to include cayenne, ginger, turmeric, yucca, Devil's claw, nettle leaf, Black Cohosh, alfalfa and celery seeds.
U.S. Pat. No. 5,888,514 (Weisman) discloses a composition for treating bone or joint inflammation in mammals, wherein the composition contains a systemically absorbable cartilage and an amninosaccharide and may optionally contain, among other ingredients, one or more extracts of an herb of the genus Withenia, of the bark of an herb of the genus Salix, or of a root of an herb of the genus Panax.
U.S. Pat. No. 5,908,628 (Hou) discloses compositions for treating osteoarthritis and rheumatoid arthritis, containing talc, silkworm excrement, and ingredients of plants of species of the genera Stephania, Coix, Pinellia, Prunus, Phellodendron, Sophora, Tetrapanax, Stemona, Glycyrrhiza, Tripterygium, Forsythia, and Siegesbeckia.
U.S. Pat. No. 5,788,971 (Togasaki) discloses an active oxygen free radical scavenging agent composed of green tea leaf extract containing epigallo catechin gallate and sunflower seed extract containing chlorogenic acid.
U.S. Pat. No. 5,854,291 (Laughlin, et al.) discloses a topically-applied pain reliever composition for treating such discomforts as arthritis pain, composed of capsaicin and, optionally, a plant extract selected from the group consisting of nettle extract, yarrow extract, coltsfoot extract, birch extract, rosemary extract, horsetail extract, ginger extract, chamomile extract, comfrey extract, lavender extract, and bergamot extract.
U.S. Pat. No. 5,910,307 (Kwak, et al.) discloses a combined medicinal plant composition for alleviating acute/chronic inflammation, composed of Clematis Radix, Trichosanthes root, and Prunella Herba (which contains oleanolic acid ursolic acid) in a certain ratio. The composition is also useful for inhibiting platelet/whole blood aggregation and inflammation-inducing enzymes (5-lipoxgenase, cylooxygenase-1 and cylooxygenase-2) and for scavenging toxic active oxygen species.
According to various studies, ocimum sanctum (holy basil) possesses significat anti-inflammatory properties and is capable of blocking both the cyclooxygenase and lipoxygenase pathways of arachidonate metablism. See e.g., J. Ethnopharmacol. April 1999; 65(1);13-9, Evaluation of the Gastric Antiulcer Activity of Fixed Oil of Ocimun Sanctum (Holy Basil), Singh, S. Majundar DK College of Pharmacy, University of Delhi, India; Indian J. Exp. Biol. October 1998; 36(10): 1028-31, Comparative Evaluation of Antiinflammatory Potential of Fixed Oil of Different Species of Ocimun and Its Possible Mechanism of Action, Singh S. College of Pharmacy (University of Delhi), Pushp Vihar, India; J. Ethnopharmacol. October 1996; 54(1):19-26, and Evaluation of Anti-Inflammatory Potential of Fixed Oil of Ocimum Santum (Holy Basil) and Its Possible Mechanism of Action, Singh, S., Majunbar D K, Rehan H M College of Pharmacy (University of Delhi), New Delhi, India. The marker constituents of ocimum sanctum, i.e., ursolic acid and oleanolic acid (less active) have been found to a significant COX-2 inhibitory effect. See, for example, Indian J. Exp. Biol. April 1997, 35(4):380-3, Evaluation of Antiinflammatory Activity of Fatty Acids of Ocinum Sanctum Fixed Oil, Singh S., Majumdar DK College of Pharmacy (University of Delhi) Pushp Vihar, New Delhi, India; and FEBS Lett. Mar. 16, 1992; 299(3):213-7, Characterization of Uroslic Acid as a Lipoxygenase and Cyclooxygenase Inhibitor Using Macrophages, Platelets and Differentiated HL60 Leukemic Cells, Najid A., Simon A., Cook J., Chable-Rabinovitch H., Delage C., Chulia A J, Rigaud M. CJF INSERM 88-03, Faculte de Medecine, Universite de Limoges, France; J. Nat. Prod. October 1998; 61(10); 1212-5, Ursolic Acid from Plantago Major, a Selective Inhibitor of Cyclooxygenase-2 Catalyzed Protaglandin Biosynthesis, Ringbom T., Segura L., Noreen Y., Perera P., Bohlin L. Divison of Pharmacognosy, Department of Pharmacy, Biomedical Centre, Uppsala University, Box 579, S-751 223 Uppsala, Sweden; Cancer Res. Feb. 15, 1998; 58(4):717-23 Novel Triterpenoids Suppress Inducible Nitric Oxide Synthase (iNOS) and Inducible Cyclooxygenase (COX-2) in Mouse Macrophages, Suh N., Honda T., Finlay H. J., Barchowsky A., Williams C., Benoit N. E., Xie Q. W., Nathan C., Gribble G. W., Sporn M. B., Department of Phamacology and Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, N.H. 03755 USA; Indian J. Exp. Biol. December 1996; 34(12):1212-5, Chemical and Pharmacological Studies on Fixed Oil of Ocimun Sanctum; Singh S., Majumdar D. K., Yadov M. R., College of Pharmacy (University of Delhi) Pushp Vihar, India.; J. Ethnopharmacol November 1987, 21(2):153-63, Ocinum Sanction: An Experimental Study Evaluating Its Anti-Inflammatory, and Analgesic and Antipyretic Activity in Animals; Godhwani, S., Godhwani, J. L., Vyas D. S., Department of Phamacology and Experimental Therapeutics, Sandar Patel Medical College, Rajasthan, India.
Curcumin, a major principal of turmeric, has been found to directly inhibit the activity of COX-2. See, e.g., Carcinogenesis March 1999, 20(3):445-51, Curcumin Inhibits Cyclooxgenase-2 Transcription in Bile Acid- and Phorbol Ester-Treated Human Gastrointestinal Epithelial Cells, Zhang F., Altorki N. K., Mestre J. R., Subbaramiah K., Dannenberg A. J., Department of Cardiothoracic Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York 10021, USA. See also, e.g., Agents Actions October 1982, 12(4):508-15, Anti-Inflammatory and Irritant Activities of Curcumin Analogues in Rats, Mukhopadhyay A., Basu N., Ghatak N., Gujral P. K; and Int J Clin Pharmacol Ther Toxicol December 1986, 24(12):651-4, Evaluation of Anti-Inflammatory Property of Curcumin (Diferuloyl Methxane) in Patients with Postoperative Inflammation, Satoskar R. R., Shah S. J., Shenoy S. G.
Melatonin, a constituent of ginger, has been found to exert potent anti-inflammatory effects via COX-2 inhibition. See, e.g., J Pineal Res August 1999, 27(1):9-14, Regulation of Prostaglandin Production in Carrageenan-Induced Pleurisy by Melatonin, Cuzzocrea S, Costantino G., Mazzon E., Caputi A. P., Institute of Pharmacology, School of Medicine, University of Messina, Italy; Biochem Mol Biol Int March 1995, 35(3):627-34, Identifacation of Melatonin in Plants and Its Effects on Plasma Melatonin Levels and Binding to Melatonin Receptors in Vertebrates, Hattori A., Migitaka H., Iigo M., Yamamoto K., Ohtani-Kaneko R., Hara M., Suzuki T., Reiter R. J., Department on Anatomy, St. Marianna University School of Medicine, Kawasaki, Japan. See also Biomed Biochim Acta 1984; 43(8-9):S335-46, Aqueous Extracts of Onion, Garlic and Ginger Inhibit Platelet Aggregation and Alter Arachidonic Acid Metabolism, Srivastava K. C.; and Cancer Res Mar. 1, 1996; 56(5):1023-30, Inhibition of Tumor Promotion in SENCAR Mouse Skin by Ethanol Extract of Zingiber Officinale Rhizome, Katiyar S. K., Agarwal R., Mukhtar H., Department of Dermatology, Skin Diseases Research Center, University Hospitals of Cleveland, Case Western Reserve University, Ohio.
Shogaol, a pungent component of ginger, has been found to inhibit cyclooxygenase. Reference is made, e.g., to Nippon Yakurigaku Zasshi October 1986; 88(4):263-9, Pharmacological Studies on Ginger. IV. Effect of (6)-Shogaol on the Arachodonic Cascade, Suekawa M., Yuasa K., Isono M., Sone H., Ikeya Y., Sakakibara I., Aburada M., Hosoya E.
Another constituent of ginger, eugenol, has also been found to be a 5-lipoxygenase inhibitor and to possess potent anti-inflammatory and/or anti-rheumatic properties. Reference is made, e.g., to Pharmacology November 1994, 49(5):314-8, Suppressive Effects of Eugenol and Ginger Oil on Arthritic Rats, Sharma J. N., Srivastava K. C., Gan E. K., Department Pharmacology, School of Medical Sciences, University of Science, Malaysia, Kelantan.
According to the USDA database, green tea contains six constituents having cyclooxygenase-inhibitor activity. According to the Napralert database, green tea contains fifty one constituents having anti-inflammatory activity. The polyphenos in green tea were found to cause a marked reduction in cyclooxygenase-2. Reference is made, e.g., to Proc Natl Acad Sci USA Apr. 13, 1999; 96(8):454-9, Prevention of Collagen-Induced Arthritis in Mice by a Polyphenolic Fraction from Green Tea, Haqqi T. M., Anthony D. D., Gupta S., Ahmad N., Lee M. S., Kumar G. K., Mukhtar H., Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106. See also Photochem Photobiol November 1993, 58(5):695-700, Protection Against Ultraviolet-B Radiation-Induced Local and Systemic Suppression of Contact Hypersensitivity and Edema Responses in C3H/HeN Mice by Green Tea Polyphenols, Katiyar S. K., Elmets C. A., Agarwal R., Mukhtar H., Department of Dermatology, University Hospitals of Cleveland, Case Western Reserve University, Ohio 44106.
In addition, a group of compounds identified as flavan-3-ol derivatives (+)-catechin, rich in green tea, have been identified as COX-1 and COX-2 inhibitors, See, e.g., Planta Med August 1998; 64(6):520-4 Flavan-3-ols isolated from some medicinal plants inhibiting COX-1 and COX-2 catalysed prostaglandin biosynthesis. Noreen Y., Serrano G, Perera P., Bohlin L Department of Pharmacy, Uppsala University, Sweden; J Nat Prod January 1998; 61(1):8-12 Two new isoflavones from Ceiba pentandra and their effect on cyclooxygenase-catalysed prostaglandin biosynthesis. Noreen Y., el-Seedi H, Perera P., Bohlin L Department of Pharmacy, Uppsala University, Sweden; J Nat Prod January 1998; 61(1):2-7 Development of a radiochemical cyclooxygenase-1 and -2 in vitro assay for identification of natural products as inhibitors of prostaglandin biosynthesis. Noreen Y., Ringbom T., Perera P., Danielson H, Bohlin L Department of Pharmacy, Uppsala University, Sweden.
Salicylic acid, another constituent of green tea, also has been found to be a COX-2 inhibitor. Reference is made, e.g., to Mol Pharmacol June 1997, 51(6):907-12, Sodium Salicylate Inhibits Cyclo-Oxygenase-2 Activity Independently of Transcription Factor (Nuclear Factor KappaB) Activation: Role of Adrachidonic Acid, Mitchell J. A., Saunders M., Barnes P. J., Newton R., Belvisi M. G., Department of Anaesthesia and Critical Care Medicine, The Royal Brompton Hospital, London, England.
Berberine, found in barberry and Chinese goldthread, has been found to inhibit COX-2 without inhibiting COX-1 activity. Reference is made, e.g., to J Ethnopharmacol August 1999; 66(2):227-33 Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells; Fukuda K, Hibiya Y, Mutoh M, Koshiji M, Akao S, Fujiwana H Department of Oriental Medicine, Gifu University School of Medicine, Japan; and Biol Pharm Bull August 1998; 21(8):814-7 Inhibitory effect of Coptidis Rhizoma and Scutellariae Radix on azoxymethane-induced aberrant crypt foci formation in rat colon. Fukutake M, Yokota S, Kawamura H, Iisuka A, Amagaya S, Fukuda K, Komatsu Y Central Research Laboratories, Tsumura & Co., Ibaraki, Japan.
According to the USDA database, oregano is the source of the largest number of anti-inflammatory compounds.
Scutellaria baicalensis has been found to possess anti-inflammatory properties. See, e.g., Planta Med April 1995; 61(2):150-3 Pharmacological effects of methanolic extract from the root of Scutellaria baicalensis and its flavonoids on human gingival fibroblast. Chung C P, Park J B, Bae KH College of Dentistry, Seoul National University, Korea.
Other mediators of inflammation include oxygen-derived free radicals. Free radicals degrade hyaluronic acid, modify collagen and perhaps proteoglycan structure and/or synthesis, alter and interact with immunoglobulins, activate degradative enzymes and inactivate their inhibitors, and possibly participate in chemotaxis. It is desirable to provide a means for scavenging and detoxifying free radicals before they reach the affected area.
Ocimum sanctum (holy basil) has been found to possess antioxidant properties. Reference is made, for example to Free Radic Res August 1997; 27(2):221-8 Evaluation of Antoxidant Effectiveness of a Few Herbal Plants, Maulik G., Maulik N., Bhandari V., Kagan V. E., Pakrashi S., Das D. K., University of Connecticut School of Medicine, Farmington, Conn. 06030-1110, USA; and Radiat Res January 1999; 151(1):74-8, In Vitro Radioprotection by Ocimum Flavenoids: Survival of Mice, Uma Devi P., Ganasoundari A., Rao B. S., Srinivasan K. K., Department of Radiobiology, Kasturba Medical College, Manipal, India.
Rosemary is an antioxidant which may reduce COX-2 expression. Reference is made, e.g., Cancer Res. June 1, 1998; 58(11):2323-7 Antioxidants reduce cylooxygenase-2 expression, prostaglandin production, and proliferation in colorectal cancer cells. Chinery R, Beauchamp R D, Shyr Y, Kirkland S C, Coffey R J, Morrow JD Department of Medicine, The Vanderbilt Cancer Center, Vanderbilt University Medical Center, Nashville, Tenn. 37232, USA; J Clin Invest April 1995;95(4):1669-75 Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-alpha, and lipopolysaccharide. Ferg L, Xia Y, Garcia G E, Hwang D, Wilson CB Department of Immunology, Scripps Research Instiute, La Jolla, Calif. 92037, USA.
Turmeric and curcumin have been found to offer as much antioxidant effect as vitamin E. Reference is made, for example to Free Radic Biol Med Jan. 1, 1998; 24(1):49-54, Effect of Tumeric, Tumerin and Curcumin on H2O2-induced Renal Epithelial (LLC-PK1) Cell Injury; Cohly H. H., Taylor A., Angel M. F., Salahudeen A. K., Department of Surgery (Plastic), University of Mississippi Medical Center, Jackson 39216, USA.
Scutellaria baicalensis has the ability to scavenge free radicals, Reference is made, e.g., to Z Naturforsch [C] November-December 1997;52(11-12):817-23 Antioxidant activity of flavones from Scutellaria baicalensis in lecithin liposomes. Gabrielska J, Oszmianski J, Zylka R, Komorowska M Department of Physics and Biophysics, Agricultural University, Norwida, Wroclaw; and Res Commun Mol Pathol Pharmacol October 1995;90(1):103-14 Protection by baicalein against ascorbic acid-induced lipid peroxidation of rat liver microsomes. Gao D, Sakurai K, Chen J, Ogiso T Shenyang College of Pharmacy, P.R. China.
Although herbal-containing compositions for reducing inflammation are know, it is continually desirable to provide alternative herbal compositions capable of reducing inflammation, particularly by inhibiting COX-2.
Accordingly, a primary object of this invention is to provide an herbal composition capable of effectively reducing bone and joint inflammation by inhibiting COX-2.
Another object of this invention is to provide an herbal composition capable of reducing inflammation while avoiding the side effects associated with traditional drug therapy.
A further object of this invention is to provide a COX-2-inhibiting herbal composition which not only has anti-inflammatory properties by also antioxidant properties.
A still further object of this invention is to provide an anti-inflammatory, COX-2-inhibiting herbal composition wherein the herbal extracts used are prepared without chemical solvents.
Yet another object of this invention is to provide an herbal composition having the characteristics set forth in the preceding objects, wherein the composition can be orally, topically or parenterally administered.
A further object of this invention is to provide methods of reducing inflammation using an herbal composition having the characteristics set forth in the preceding objects.
These objects and others are achieved in the present invention.